Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity

Abstract By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3′,4′,5′-trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel–Crafts reaction based on chemical modification of Combrestatatin A-4 ( CA-4 ). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure–activity relationship study indicated that compound 8a with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series. 8a was found to exhibit the IC 50 values of 8.4–26.4 nM in five human cancer cell lines, with comparable inhibition effects to CA-4 . Moreover, 8a showed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over-expressing multidrug resistant cell lines. Mechanism studies revealed that 8a could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent, 8a was also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore, 8a significantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that 8a was a promising microtubule targeting antitumor agent.